HBV-DNA Suppression and Disease Course in HBV Cirrhosis Patients on Long-Term Lamivudine Therapy

Abstract

In hepatitis B virus (HBV) cirrhosis patients on long-term lamivudine (LAM), the relationships between HBV suppression, development of viral resistance and disease outcome are unclear. We analysed the dynamic of serum HBV-DNA and its relationship with the clinical course of 59 patients (52 males, mean age 51.4 ±8.4 years, 12 HBeAg positive and 47 HBeAg negative, and 57 genotype D and two genotype A) with cirrhosis (45 in Child-Turcotte-Pugh class A) and high levels of serum HBV-DNA (median 14.7x107 genomes/ml) treated with LAM [median (range): 44 (15–78) months]. A total of 50 patients (84.7%) achieved a virological response (serum HBV-DNA negative by PCR) during the first 6 months of therapy, and nine (13.3%) achieved a reduction in viral load of >3 log10. Mutations in the YMDD motif of HBV polymerase were documented in 26 patients [median (range) 18: (7–42) months]. At the time of the emergence of mutants, 22 patients had HBV-DNA <105 genomes/ml and normal alanine aminotransferase (ALT) levels. The appearance of virological resistance was followed by an increase of HBV-DNA to ≥105 genomes/ml and of ALT values in 19 out of 26 patients [median (range): 8 (3–19) months]. Event-free survival was significantly longer ( P=0.001) in patients who maintained virological suppression than in those who did not have a complete virological response or suffered a breakthrough. Patients with advanced cirrhosis were more likely to develop liver failure after the emergence of YMDD mutants. The risk of development of hepatocellular carcinoma in patients with compensated cirrhosis and YMDD mutations was maintained, regardless of HBV-DNA serum levels. Profound and maintained HBV-DNA suppression correlates with a better outcome. Early identification of LAM resistance mutations allows switching to other antivirals before liver decompensation or hepatocellular carcinoma development.

Management of Chronic Hepatitis B: Consensus Guidelines

“…This benefit is lost if lamivudine resistance develops, implying that it is the suppression of viral replication that mediates the response. Patients with cirrhosis who develop lamivudine resistance have worse survival than those whose infection remains sensitive to lamivudine (66), again suggesting that the improvement in outcome is mediated through viral suppression. There are also data suggesting that improvement in histology following antiviral therapy is correlated with the degree of viral suppression, rather than with any specific agent (67).…”